Photochemotherapy or photodynamic therapy is a technique based on the discovery that cancer cells treated with certain chemicals will die when exposed to light. This technique consists in the administering of a tumor-localizing photosensitizer (photochemotherapeutic) followed by the irradiation of the targeted tumor site with photoactivating light of a suitable wavelength, in order to activate the photosensitizing agent that in turn converts oxygen into cytotoxic forms, whereby the affected cells are killed or their proliferative potential diminished.
5-ALA is known to specifically induce the in-situ formation of high amounts of photoactive porphyrins in neoplastic and (non-) neoplastic cells with high cellular turnover. Beside the use of 5-ALA for treatment by PDT the use of its ability to induce preferential accumulation of photoactive porphyrins in neoplasia was suggested for improving detection of neoplastic lesions in order to guide biopsies, improve surgery, or allow for appropriate patient's management. However, the clinical development of 5-ALA-mediated phototherapy and fluorescence photodetection (FD) of neoplastic diseases, which are those of the most selective cancer treatment techniques, have been hampered by the limited local bioavailability of 5-ALA. In fact, the short plasma half-life of 5-ALA and its low bioavailability largely hinders its application for neoplastic lesions that are not accessible by topical administration.
The development of 5-ALA derivatives and especially 5-ALA esters (WO 96/28412, WO 02/10120, Fotinos et al., 2006, Photochemistry and Photobiology, 82: 994-1015) such as methylaminolevulinate (MAL) and hexylaminolevulinate (HAL), led to market approval of those for the treatment of actinic keratinosis and difficult-to-treat basal cell carcinoma (Metvix®; Galderma, Switzerland) and for improving detection of superficial bladder cancer (Hexvix®; Photocure ASA, Oslo, Norway), respectively. Acid addition salts of 5-ALA and 5-ALA derivatives (WO 2005/092838) have been further developed for improving their physicochemical properties such as for increasing their stability (e.g. lower hygroscopicity), notably for topical formulations (e.g. creams) as compared to the corresponding hydrochloride salts.
However, the use of 5-ALA esters remains restricted to organs that are accessible by topical administration as they have been shown to be unstable in the gastrointestinal tract when given orally or in the blood plasma. Their systemic use has shown to induce acute toxicity after bolus injections in numerous in vivo models (Perotti et al., 2002, British Journal of Cancer, 87: 790-795; Di Venosa et al., 2006, Cancer Chemotherapy and Pharmacology, 58, 478-486 or Fotinos et al., 2006, Photochemistry Photobiology, 82: 994-1015). Furthermore, the systemic use of 5-ALA esters induces the formation of porphyrins in a much less effective way than 5-ALA. Finally, those compounds have been shown to be poorly stable overtime.
Therefore, important life-threatening diseases including brain cancer, prostate cancer, mama carcinoma, breast cancer, ovarian cancer, lung cancer, and lymphoma can hardly be detected/treated by 5-ALA-mediated phototherapy technology. Thus, there is a big need for alternative photochemotherapeutic agents or agents for fluorescence photodetection via parenteral routes, namely oral, intravenous, intraperitonal, intramuscular, or subcutaneous.